Tertiary-aminoalkyl 4-alkylamino-2-benzyloxybenzoates and debenzylation thereof



Patented Dec. 15, 1953 UNITED STATES PATENT OFFICE TERTIARY-AMINOALKYL 4-ALKYLAMINO-2- BENZYLOXYBENZOATES AND DEBENZYL- ATION THEREOF Raymond 0. Clinton, North Greenbush, and Stanley 0. Laskowski, Menands, N. Y., assignors to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Original application June 17', 1950,

Serial No. 168,842. Divided and this application August 17, 1951, Serial No. 242,422

18 Claims.

IIIHRII where R" is a lower alkyl radical, X is a lower alkylene radical and NRR' is a lower aliphaticlike tertiary-amino radical, exhibit valuable pharmacological properties. These esters, preferably in their form of water-soluble acid-addition salts, have been found to possess outstanding local anesthetic activity.

In the above general formula, the lower alkyl radical designated as R, preferably has from 1-6 carbon atoms, including methyl, ethyl, n-propyl, n-butyl, isobutyl, Z-amyl, n-hexyl, and the like. The lower alkylene radical represented by X has preferably 2-4 carbon atoms, and has its two free valence bonds on different carbon atoms. Thus X includes such examples as CH2CH2-, -CI-I2CH2CH2,

the like. lhe lower aliphatic-like tertiaryamino radical shown above as NRR' comprehends lower dialkylamino radicals where R and R are lower alkyl groups, alike or different, and each alkyl group having preferably 1-6 carbon atoms, such diallrylamino radicals including dimethylarnino, diethylamino, ethylmethylamino, diisopropylamino, di-n-butylamino, di-n-hexylamino and the like. Further, the lower aliphatic-like tertiary-amino radical designated as NRR' encompasses those radicals where R and R are joined directly or through an oxygen atom to form saturated N-heteromonocyclic radicals having 5- 6 ring atoms, illustrated by examples such as lpiperidyl, .Z-methyl-l-piperidyl, 3-ethyl-1-piperidyl, e-methyl-l-piperidyl, 2,6-dimethyl-1-piperidyl, l-pyrrolidyl, 2-methyl-l-pyrrolidyl, 2,5-dimethyl-1-pyrrolidyl, 4-morpholinyl, and the like.

2 The above basic esters are prepared by esterifying 4-nitro-2-hydroxybenzoic acid to produce the tertiary-aminoalkyl 4-nitro-2-hydroxybenzoate having the formula where X and NRR have the meanings given hereinabove, and reducing said basic 4-nitro-2- hydroxybenzoate to the corresponding tertiaryaminoalkyl 4-amino-2-hydroxybenzoate and then alkylating said 4-amino ester to form the related tertiary-aminoalkyl 4alkylamino 2 hydroxybenzoate. A specific illustration of this procedure is the formation of 2-dimethylaminoethyl 4-nbutylamino-2-hydroxybenzoate by esterifying 4- nitro-Z-hydroxybenzoic acid to produce 2-dimethylaminoethyl 4-nitro 2 hydroxybenzoate and reducing the latter to form 2-dimethylaminoethyl. 4-amino-2-hydroxybenzoate and a1kylating said e-amino ester to produce Z-dimethylaminoethyl 4-n-butylamino-2-hydroxybenzoate We carried out the esterification of 4-nitro-2-hydroxybenzoic acid to produce the'corresponding tertiary-aminoalkyl ester in various ways. In one procedure, the 4-nitro-2-hydroxybenzoic acid was reacted with a tertiary-aminoalkyl halide. In another procedure, a lower alkyl -nitro-Z-hydroxybenzoate was transesterified with a tertiaryaminoalkanol. In still another procedure, the 4-nitro-2-hydroxybenzoic acid was first treated with a haloalkanol to produce a haloalkyl ester which was reacted with a secondary amine to yield the desired tertiary-aminoalkyl ester. Thus, in the above specific illustration, 2-dimethylaminoethyl 4-nitro 2.-hydroxybenzoate is. prepared by reacting 4-nitro-2-hydroxybenzoic acid with Z-dimethylaminoethyl chloride; by reacting methyl 4-nitro-2-hydroxybenzoate with Z-dimethylaminoethanol; or by first reacting e-nitro-fz-hydroxybenzoic acid with ethylene chlorohydrin and treating the resulting 2-chloroethyl 4-nitro-2- hydroxybenzoate with 'dimethylamine.

ihe reduction of the tertiary-aminoalkyl e nitro-Z-hydroxybenzoates to the corresponding 4-amino-2-hydroxyhenzoates was carried out both by chemical methods and. by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. Catalysts suitable when catalytic hydrogenation is used include Raney nickel, platinum, palladium, or other catalysts generally effective to catalyze hydrogenation of nitro groups to amino groups.

The alkylation of the basic ii-amino esters to produce the related tertiary-aminoalkyl d-alkyh amino-2-hydroxybenzoates was preferably carried out by reductively alkylating with an alkanal. An illustration is the formation of 3-(2-1nethyll-pyrrolidyl) propyl 4n-propylamino-2-hydroxy benzoate by treating a mixture of the corresponcling basic 4-amino-2-hydroxybenzoate and propionaldehyde with chemical reducing agen s, such as zinc dust and acetic acid, iron and acetic acid, or with hydrogen under pressure using catalysts such as platinum, palladium, Raney nickel, or other catalysts generally efiective in reductive alkylations using aliphatic aldehydes.

Our tertiary-aminoalkyl l-alkylamino-Z-hydroxybenzoates are therapeuticallyactive wheth" or employed as the free bases or as their salts with relatively non-toxic organic or inorganic acids. We found it convenient to isolate the basic esters their hydrochlorides, However, other acid-addition salts are within the scope of our invention. Such additional salts include the hydrobromides, sulfates, phosphates, citrates, sulfamates, tartra-tes, succinates, acetates, benzeates, oleates, and the like.

Specific embodiments of our invention are illus trated in the following paragraphs:

1. Tertiary-aminoalkyl4-nitro-2- hydrorybenzoates These basic esters were prepared from 4-nitro- 2-hydroxybenzoic acid by the following esterification variants: by the reaction of 4-nitro-2-hydroxybenzoic acid with a tertiary-aminoalkyl halide; by the reaction of a lower alkyl 4-nitro-2- hydroxybenzoate with a tertiary-aminoalkanol; or by the reaction of 4nitro-2-hydroxybenzoic acid with a haloalkanol followed by treatment of the resulting haloalkyl ester with a secondary amine.

The first variant is illustrated by the following preparation of 2-cliethylaminoethy1 i-nitr-2- hydroxybenzoate hydrochloride: To a stirred, refluxing solution of 137.5 g. of 4-nitro-2-hydroxybenxoic acid in 800 ml. of isopropanol was added drcpwise 110 g. of Z-diethylaminoethyl chloride during the course of one and one-half hours. The resulting heterogeneous mixture was stirred and refluxed for an additional seven hours, cooled, and the dense white precipitate was collected. The filtrate was evaporated to dryness in vacuo and the resulting residue was triturated with acetone. The acetone-insoluble material was combined with the original precipitate and the material was recrystallized several times from ethanol in the presence of a small amount of anhydrous hydrogen chloride. There was obtained 161.4 g. (67.7%) of 2-diethylsminoethyl 4-nitro-2-hydroxybenzoate hydrochloride, M. P. 179.6-180.4 C. (corn), crystallizing in white needles.

The second variant of reacting a lower alkyl -nitro 2 hydroxybenzoate with a tertiaryaminoalkanol is illustrated by the following preparation of B-(Z-methyl-l-piperidyl)propyl 4- nitro-2-hydroxybenzoate hydrochloride: A mixture of 84.5 g. of ethyl 2-hydroXy-4-nitrobenzoate, 70.8 g. of 3-(2-methy1-1-piperidyl)propanol, 700

m1. of dry toluene and 280 mg. of sodium methoxide was slowly distilled through an eflicient fractionating column. The evolution of ethanol was slow, requiring forty-eight hours for completion. The residue was evaporated in vacuo and the resulting viscous oil was dissolved in ethyl acetate and treated with an excess of ethereal hydrogen chloride. The resulting thick heavy oil was separated by decantation and dissolved in dry acetone. On scratching and cooling this solution a dense white precipitate appeared. Several recrystallizations from isopropanol gave 55.7 g. (39%) of 3-(2-methyl-l-piperidyl)propyl l-nitro-.Z-hydroxybenzoate hydrochloride, crystallizing in needles, M. P. 173.0l73.8 C. (corn) The third variant for preparing the tertiaryarninoalkyl 4-nitro-Z-hydroxybenzoates is illustrated as follows: A mixture of one mole of 4- nitro-2-hydroxybenzoic acid and three moles of ethylene chlorohydrin was heated to reflux and dry hydrogen chloride was passed into the reaction mixture for eight hours. The excess ethylene chlorohydrin was removed by distilling in vacuo and the residue when crystallized from absolute ethanol yielded Z-chloroethyl i-nitro-Z- hydroxybenzoate, M. P. 87.4-8B.4 C. (corn). The corresponding Z-brornoethyl ester, M. P. 74.7-74.9" C. (cont), resulted when ethylene bromohydrin was used in place of ethylene chlorohydrin. A mixture of one mole of Z-chloroethyl (or 2-bronioethyl) 4-nitro-2-hydroxybenzoate and two moles of diethylamine and 1500 ml. of toluene was refluxed for twenty-four hours. After removal of the solvent by distilling in vacuo, the residue was dissolved in hydrochloric acid, the acidic solution was treated with decolorizing charcoal and filtered. The filtrate was made alkaline with potassium carbonate and the mixture was extracted with ethyl acetate. After removal of the ethyl acetate by distilling in vacuo, the residue was dissolved in absolute ethanol and the alcoholic solution was treated with excess hydrogen chloride in ether. Addition of excess ether precipitated the basic ester salt, Z-diethylaminoethyl 4-nitrc-2-hydrox benroate hydrochloride, which was recrystallized from isopropanol.

Other tertiary-aminoalkyl 4-nitro-2-hydroxybenzoate hydrochlorides prepared according to 0 the foregoing procedures including those given in Table A.

TABLE A Additional tertiary-aminoalkyl 4-nitro-2-hydroxybenzoate hydrochlorides which can be pretune of inner salts, with the formula 2*. Tertiary aminoalkyl'4 amino-2 hydroxybeneoates These esters are prepared byre'ducing' thehereinabovedescribed tertiary aminoalkyl -nitro- 2-hydroxyb'enzoates. This reduction is carried out either by chemical means or by catalytic hydrogenation methods.

Exemplary of the chemical method is the following preparation of z-(zfi-dimethyl-l-piperidyllethyl l--amino'--2-hydroxybenzoate:. To a stirred boiling mixture of 90 g. of iron powder, G ml. of water, 300 ml. of ethanol and 1 ml. of concentrated hydrochloric acid. was gradually added in portions 80.? g. of 2.-(2,6-di'methyl--1- piperidyhethyl Z-hydroxyA-nitrobenzoate hydrochloride. Each addition produced an ex.- othermic reaction. When the addition had. been completed, the mixture was stirred at the boiling point for twenty minutes. While continuing stirring and heating, to 40 g. of solid sodium bicarbonate was cautiously added, and the resulting mixture was stirred and heated an addi tional ten minutes; The mixture was filtered hot and the filter cake washed well with hot ethanol. The combined filtrates were concentrated in vacuo until all ethanol was removed. The residual aqueous suspension of the crystalline base was cooled and filtered, and the precipitate was washed well with cold water. The precipitate crystallized from n-heptane in rosets of beautiful long' slender needles of 2-(2,6-dimethyl-l-piperidyl) ethyl 4 amino 2 hydroxybenzoate, M. P. 1l1.0'-lll.6' C. (corr.). The phosphate of this basic ester was prepared from mole equivalents of base and phosphoric acid (Hal-04) in absolute ethanol and recrystallized by dissolving in a minimum amount of" hot water, filtering and slowly dilutingwith hot absolute ethanol. The resulting salt; 2-(2,6'-diinethyl--ipiperidyliethyl 4i amino 2 -hydroX-ybenzoate phosphate, melts at 19717-2000 C. (born).

A specific illustration of the catalytic hydrogenation method of preparing our tertiaryarninoalkyl l.-aminc-Z-hydroxybenzoates is the following synthesis of 3-(l-piperidyDpropyl 4- aroino-Z-hydroxybenzoater A mixture ofv 10.0 g. of 3--( 1.-piperi'dyl)propyl. 4-nitro-2-hydroxybenzoate hydrochloride, 50D mg. of platinum oxide and 150 ml. of 50% aqueous ethanol was hydrogenated in a Parr-Burgess hydrogenatorat 25-45" C. and 20-50 lbs. pressure. The theoretical amount of hydrogen was absorbed in fifteen to twenty minutes. The mixture was filtered and evaporated to dryness in vacuo. The residual white solid was crystallized from ethanol to give a high yield of 3-(1.-piperidyl)propy1 4-amino- Z-hydroxybenzoate hydrochloride, M. P. 239.5- 240.2 C. (corn). The phosphate salt of this basic ester was prepared as follows: 3-(1-piperi'dyDpropyl l-amino-z-hydroxybenzoate hydrochloridewas"converted to the crystalline base by treatment of an aqueous solution thereof with an excess ofsodium carbonate solution. The resulting base when treated with a one mole proportion of phosphoric acid in absolute alcohol solution readily yielded 3-(1-piperidyDpropyl -amino-Z-hydroxybenzoate phosphate, forming rosets of large blunt needles from ethanol, M. P. 204.75-205.0 C. (dec.) (corn).

Other tertiary aminoalkyl 4-amino-2-hydroxybenzoates. prepared according to the. above procedures include those given in Table 13.

a NCBHQ l-piperidyL. N (35E; 2 =2methyl-l -piperidy1. -Terttg=%ig gggyl is} H s 2N( a) or B-d'imcth lamin -2- A d NGiHgO=4-morpholinyli y 0 pmpy] llithdecompositiom Monohydrochloride melts at 2259-2255 0. (com). 'l/lonohydrochloride; of Crystalhzedlrom dilutecthanol as the monohydratc, M. P. 87-90 Additional tertiary-aminoallzyl 4-amino--2hydroxybenzoates which can be prepared according to the. above procedures include the following: 4 -'dimethylaminobutyl 4 amino-Z-hydroxybenzoate; 2 di n butylaminoethyl 4-amino-2-hydroxybenzoate; 2-(l-pyrro-lidyl)ethyl el-amino- 2- hyd'roxybenzoate; 3- (2-methyl-l-pyrrolidyhpropyl' 4-amino-Z-hydroxybenzoate; and. 2.-(2.,5- dimethyl L-py-rrolidyl'). ethyl 4-amino-2-hydroxybenzoate.

The; foregoing tertiary-aminoalkyl l-amino-Z- hydroxybenzoates, are also conveniently prepared from. 4-nitro-2-hydroxybenzoic acidv or its lower alkyl. esters through the Z-benzyloxy derivatives. according to the steps illustrated. in the following equation, wherein R is a loweralkyl 7 group and X and NRR' have the meanings given hereinabove:

fled in Step II to yield the desired -nitro-Z- I benzyloxybenzoic acid or by benzylating a lower alkyl 4-nitro-2-hydroxybenzoate (Step I) to form a lower alkyl -nitro-Z-benzyloxybenzoate (A'), which in Step II is saponified to the desired acid (B). l-nitro-2-benzyloxybenzoic acid is then esterified in Step III to produce the corresponding tertiary-aminoalkyl 4-nitro-2-benzyloxybenzoate (C) which in Step 1V is reduced to the corresponding tertiary-aminoalkyl 4-amino- 2-benzyloxybenzoate (D). Then, in Step V, the tertiary-aminoalkyl 4-amino-2-hydroxybenzoate (E) is produced by catalytically debenzylating the basic 4-amino-Z-benzyloxybenzoate (D). Steps IV and V can be carried out in the same reaction vessel without isolating compound D when the reduction is carried out catalytically, e. g. as with palladium on charcoal. As a specific illustration of Steps III, IV, and V, i-nitro- Z-bSllZylof"-'JEIED1C acid is esterified to produce the 3-(Z-methyl-l-piperidyl)propyl 4-nitro-2-,

benzyloxybenzoate which is then reduced to the corresponding 3- (Z-methyl-l-piperidyl) propyl 4- amino-2-benzyloxybenzoate, which, in turn, is reduced to 3 (2 methyl l piperidybpropyl amino-Z-hydroxybenzoate.

We carried out esterification Step III by two variants: in one, the 4-nitro-2-benzyloxybenzoic acid was reacted with a tertiary-aminoallzyl halide; and in the other, said acid was first converted into the corresponding acid chloride which was then treated with a tertiary-aniinoalkanol. The reduction Step IV was carrie out both by chemical methods and by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate, tin and hydrochloric acid, etc. We found iron and hydrochloric acid was to be preferred. Catalysts suitable when catalytic hydrogenation was em-- ployed include Raney nickel, platinum, palladium, etc. Reduction Step V was carried out by catalytic hydrogenation, e. g. using preferably palladium, although platinum and Raney nickel can be used, the latter at higher temperatures and pressures.

The tertiary-aminoalkyl 4-amino-2-henzyloxybenzoates are useful not only as intermediates in the preparation of the corresponding 2-hydroxy esters but also as local anesthetics in their own right. The tertiary-aminoalkyl 4-amino-2- benzyloxybenzoates are therapeutically active whether employed as the free bases or as their salts with relatively non-toxic organic or inorganic acids. We found it convenient to isolate the basic 2-benzyloxy esters as their phosphates or hydrochlorides. However, other acid-addition salts are within the scope of our invention. Such additional salts include the hydrobromides, sulfates, citrates, sulfamates, tartrates, succinates, acetates, benzoates, oleates, and the like.

Specific embodiments of our invention are illustrated in the following paragraphs.

3. 4-mtro-2-benzylo:vybenzoic acid This acid was prepared from 4-nitro-2-hydroxybenzoic acid through benzyl 4-nitro-2- benzyloxybenzoate and also from a lower alkyl -nitro-2-hydroxybenzoate through a lower alkyl 4. nitro-Z-benzyloxybenzoate. Either preparation can be carried out without the isolation of the intermediate ester.

Illustrative of the procedure using a lower alkyl 4-nitro-2-hydroxybenzoate is the following where ethyl -nitro-2-hydroxybenzoate is utilized: A mixture of 84.4 g. of ethyl l-nitro-2-hydroxybenzoate, 55.6 g. of benzyl chloride, 29.6 g. of anhydrous sodium carbonate, 6.8 g. of potassium iodide, 400 ml. of ethanol and 2 ml. of water was refluxed and stirred for eight hours. To isolate the ethyl 4-nitro-2-benzyloxybenzoate the mixture was filtered hot and the insoluble material was washed with hot ethanol. The combined filtrates were concentrated to dryness in vacuo and the residue was extracted exhaustively with hot nhexane. When cooled, the extracts yielded 105.1 g. (87%) of ethyl 4-nitro-2-benzyloxybenzoate crystallizing in long rods from n-hexane, M. P. 57.0-58.5 C. (col-1:). When it was not desired to isolate the intermediate ethyl e-nitro-Z-bem zyloxybenzoate, to the above hot mixture (after the reflux period of eight hours) was added 400 ml. of water and g. of anhydrous sodium carbonate, and refluxing and stirring were continued for an additional five hours. The mixture was then filtered while hot and the precipitate, after washing well with hot ethanol, was discarded. The combined filtrates were concentrated in vacuo to remove the ethanol and the remaining aqueous solution was acidified to Congo Red with hydrochloric acid. The resulting white pre cipitate was filtered 0a, washed well with water and recrystallized twice from isopropanol. giving a yield of e-nitroQ-benzyloxybenzoate as short, thick, pale yellow needles, P. 171-172 C, Comparable yields are obtained when other lower alkyl 4-nitro-2-hydroxybenzoates, including the methyl, n-propyl and i obutyl esters, are used in place of ethyl 4-nitro-2-hydroxybenzoate.

When the above procedure was carried out, substituting 4-nitro-2-hydroxybenzoic acid for ethyl e-nitro-2-hydroxybenzoate and by using twice the amount of benzyl chloride and of sodium carbonate the intermediate benzyl 4-nitro-2- benzyloxybenzoate was obtained as small white needles from isopropanol, M. P. 96.5-98 C.

i. Tertiary-rtminoalkyl 4-m'tro-2-benzyloxybeneoates In practicing our invention we prepared these basic esters by two procedures: one, by reactin a 4-nitro-2-benzyloxybenzoyl halide with a tertiary-amionalkanol; and the other, by reacting a tertiary-aminoalkyl halide with l-nitro-2-benzyloxybenzoic acid in an appropriate solvent. The former procedure is illustrated by the following synthesis of 2-dimethyl-aininoethyl -4 -nit-ro- 2-benzyloxybenzoate: To a stirred cool mixture of 43.1 g. of pure pyridine, 64.5 a. of pure :thionyl chloride and 1-200 ml. of dry benzene, was added 148.9 g. of powdered, dry i-nitro-2-benzyloxybenzoic acid in four equal portions over'a period of twenty minutes. The heterogeneous mixture was then heated to .66 C. and allowed :to stand for one and one-half hours .at room temperature. Then, with cooling, there was added to this solution of 4-nitro-Z-benzyloxybenzoyl chloride, 4835 g. of redistilled Z-dimethylaminoethanol. After cooling, the precipitated crystals were collected and recrystallized from absolute ethanol-ethyl acetate, yielding Z-dimethylaminoethyl s-nitro- 2-benzyloxybenzoate hydrochloride, M. P. 180.2- 1813 C. (corn). 'Thefree basic ester, JZ-dimethylaminoethyl e-nitrc-2-benzyloxybenzoate, obtained by treatment of the above hydrochloride with potassium carbonate, crystallized from -di lute ethanol in pale yellow prisms, MJP. 60.0-60.7 C. (corn).

The above l-nitro-2-benzyloxybenzoy1 chloride is a yellow solid and may be'isolated before treatment with the tertiary-an1inoall:anol.

The other procedure we utilized in preparing the tertiary-aminoalkyl i-nitro-2-benzylcn ybenzoates, namely, the reaction of e-n'itro-2-benzyloxybenzoic acid with a tertiary-anzinoalkyl hailide, is illustrated by the following preparationof 3-(1-piperidyl propyl nitro-z-benzyloxybenzoate: A mixture of 54.6 g. of l-nitro-2-benzyloxybenzoic acid, 33.8 g. of 3-(l-piperidylrpropyl chloride and 669 ml. of isopropanol was refluxed for twenty hours. The clear yellow-orange solution was then taken to dryness in vacuo and the residue was taken up in water. The aqueous solution was made basic with potassium carbonate and extracted. with ethyl acetate. Afterdrying the extract, the ethyl acetate was removed in vacuo leaving a crystalline residue which when recrystallized from dilute ethanol, yielded 3-(1- piperidyDpi-opyl 4 nitro z-benzyloxybenzoate, M. P. 77.7-78.6 0. (corn). The hydrochlorideof this basic ester, which was prepared by treating a solution of the ester in ethanol with a solution of hydrogen chloride in ether, melts at 161.4- l62.5 C. (corn), when recrystallized from dilute ethanol.

Additional tertiary-aminoalkyl i-nitro-2--ben-- zyloxybenzoates, in the form of their hydrochlorides, prepared according to the above .described procedures are given in Table 10.

TABLE C M. P./O n NRR (corn) N(CH 11 158. 2-1594 N(CH3)2. c 163. 6-164. 1 N (021192.. d 133. 9-134. 7 N(C2H5)2 181. O-l81.'8 N 60 12 b 4 J84. 11-185. 0

.5. ,Tertiary-aminodllcyl 4-dm-ino-2-banzyiomy- 'benzoates illustrative of the preferred procedure for preparing these'basic esters is the following preparation of z-dimethylaminoethyl e-,amino-'2-b.enzyloxybenzoatez Toa vigorously stirredboiling mix.- ture of 1410 g, of powdered iron, .5013 ml. of ethanoil, 300 ml. of water and 51 ml. ,of concentrated hydrochloric acid was gradually added 155.3 ,g. of ,Z-dimethyilaminoethyl 4-nitro-2-benzyloxybenzoate hydrochloride. When the addition had been completed, the mixture was stirred at the boiling point for .twenty minutes, treated slowly with .410 e. if solid sodium bicarbonate, and stirred at the boiling point for an additional ten minutes. The mixture wasfiltered while hot and the insoluble material was washed well with hot ethanol. The ethanol was removed from the combined filtrates in vacuo and the residual oil was taken up in ethyl acetate. After drying, and decolorizing the solution with activated carbon, the ethyl acetate was removed in vacuo. The residual S2-dimethylaminoethyl Fl-amino- Z-benzy'loxybenzoate crystallized 'from a benzene-nhexenem'ixture in fiat white needles, P. .8455- 86..0 0. (corn). Fromthebase the following salts were preparedneutralization with the appropriate acid: s-2-dimethylaminoethyl 4-amino-2-benzyloxybenzoate phosphate, M. P. '135l5-137J5" C. (corn) .and I2-. dimethylamin0ejthyl l-amino-Z- benzyloxybenzoate .dihydrochloride, P. i1169.6 C. icorr.) (dec).

Alternatively, the .nitro group can be reduced to theamino group, without effecting .debenzylation, by catalytic hydrogenation of the base in ethanol solution using Raney nickel (but ,not palladium or platinum) catalyst, and at 'low pressures and temperature, (25 lbs, 25 'C.').

Additional tertiary-aminoalkyl i-am'ino-Z-benzyloxybenzoates, ,in the form of their phosphates or hydrochlorides, prepared according to the aboveprocedure are given in Table D.

TABLE TD Other tertiary-aminoalkyl ii-amino 2 hy- M.P./C (cor1'.) droxybenzoates which can be prepared according to the above procedures are disclosed here- Base Salt inabove under Section 2.

The foregoing tertiary-aminoallzyl 4-amino-2- 5933155 3 832:8 hydroxybenzoates and their preparation are de- 103. 0404.0 151013.? scribed and claimed in our co-pendmg applica- .4- 6.4 =1a5- gg g tion, Serial No. 168,841, filed June 1'7, 1950. 97.8-99.2

l0 6. Tertiary-aminoalkyl 4-alkylamz'no-Z-hydrory- H Tertiary-aminoalkyl is CH(CH3)CH;N(CH;); or B-dimethylamino-Z-propyl.

" Phosphate.

' Dihydrochloride.

1 illonohydrochloridc.

Additional tertiary-aminoalkyl 4-amino-2- benzyloxybenzoates which can be prepared according to the foregoing procedure include the following: 4-di1nethylaminobutyl 4-amino-2- benzyloxybenzoate; Z-di-n-butylaminoethyl 4- amino 2- benzyloxybenzoate; 2-(l-pyrrolidyl) ethyl 4-arnino-2-benzyloxybenzoate; 3-(2-methyl-l-pyrrolidyDpropyl -amino-Z-benzyloxybenzoate; and 2-(2,5-dimethyl-1-pyrrolidyl) ethyl 4-arnino-2-henzyloxybenzoate.

The above-described tertiary-aminoalkyl 4- amino-2-benzyloxybenzoates are readily debenzylated by catalytic reduction to form the corresponding tertiary-aminoalkyl 4-amino-2-hydroxybenzoates, which have been described hereinabove under Section 2. Illustrative of this procedure is the following preparation of 3-(l-piperidyDpropyl l-amino- -hydroxyhenzoate: A mixture of g. of 3-(l-piperidyDpropyl a-amino- 2-benzyloxybenzoate, 25 ml. of concentrated hydrochloric acid, 20 ml. of water, 100 ml. of 95% ethanol and 2 g. of a 7 palladium chloride-oncharcoal catalyst was shaken with hydrogen at C. and lbs. pressure until the hydrogen absorption ceased (twenty to thirty minutes). The mixture was filtered through a funnel pre-coated with diatomaceous earth and the filter-pad was washed with ethanol. The combined filtrates were neutralized with sodium bicarbonate and the alcohol was removed in vacuo. crystallized on cooling, giving a quantitative yield of 3-(1-piperidyl)propyl 4-amino-2-hydroxybenzoate, M. P. 5'7.5-58.5 C. (corr.). From the base can be prepared the hydrochloride or the phosphate, identical with those hereinabove described.

An alternative procedure is embodied in the direct conversion of Z-dimethylaminoethyl l-nitro-2-benzyloxybenzoate to 2-dimethylaminoethyl 4-amino-2-hydroxybenzoate: A mix ure of 31.3 g. of Z-dimethylaminoethyl 4-nitro-2-benzyloxybenzcate hydrochloride, 12.5 ml. of concentrated hydrochloric acid, 20 ml. of water, 100 ml. of ethanol and 4 g. of a 7% palladium chloride-oncharcoal catalyst was shaken with hydrogen, initially at room temperature and 50 lbs. pressure, and finally at 45 C. and 50 lbs. pressure. The reduction proceeded rapidly. The catalyst was removed by filtration and the resulting filtrate was processed as described above to give 2-dimethylaminoethyl 4-amino-2-hydroxybenzoate, M. P. 136.l-137.2 C. (corr.). From this base may be prepared water-soluble salts identical with those hereinabove described.

In the foregoing reductive debenzylating procedures, the palladium catalyst, which we found to be preferable, can be replaced by other catalysts such as platinum, Haney nickel, etc. Platinum is slightly less effective than palladium, and Raney nickel can be used only with higher temperatures and pressures.

The residue benzoates These basic esters were prepared by alkylating the above-described tertiary-aminoalkyl ii-amino-z-hydroxybenzoates. Exemplary of such a procedure is the following reductive alkylation using catalytic hydrogenation to produce 3-(1- piperidyDpropyl l-n-butylamino-2hydroxybenzoate: Ten grams of 3-(1-piperidyl)propyl 4-nitro-2-hydroxybenzoate was reduced as described hereinabove under Section 2. The catalyst was removed by filtration and to the filtrate was added 4.5 ml. of n-butyraldehyde and 50% mg. of platinum oxide. The mixture was again reduced on a Parr-Burgess hydrogenator at 50 lbs. and 45 C. The theoretical amount of hydrogen was absorbed in three and one-half hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness in vacuo. The residual hygroscopic yellow monchydrochloride was converted to the base with potassium carbonate in aqueous solution. The base was extracted with ethyl acetate and, after drying the extract, the ethyl acetate was removed by distillation. The resulting oil on treatment with an excess of ethereal hydrogen chloride gave 3-(1-piperidyl) propyl 4-nbutylamino-2-hydroxybenzoate dihydrochloride monohydrate, white cottony needles from isopropanol-acetone, M. P. 115.8-1l8.6 C. (corr.)

Alternatively, the reductive alkylation of the tertiary-aminoalkyl 4-amino 2 hydroxybenzoates was carried out using chemical reducing agents, as illustrated by the following preparation of 3-(Z-methyl-l-piperidyl)propyl l-n-butylamino-2-hydroxybenzoate: To a stirred refluxing mixture of 24.8 g. of S-(Z-methyl-lpiperidyl) propyl l-amino 2 hydroxybcnzoate. 22.2 g. of zinc dust, 20.9 g. of glacial acetic acid and 200 ml. of benzene was added dropwise over a period of twenty minutes a solution of 8.9 g. of n-butyraldehyde in 20 ml. of benzene. When the addition was complete, the mixture was stirred and refluxed for an additional one hour period, filtered while hot and the insoluble filter cake was washed thoroughly with dilute acetic acid and benzene. The combined filtrates were carefully adjusted to litmus-basicity with sodium hydroxide solution, mixed well, and the benzene layer was separated. After drying, the benzene extract was evaporated in vacuo. The residual golden-yellow viscous oil obtained (27.0 g.) was dissolved in dilute hydrochloric acid, the solution was washed with ether, decolorized with vated carbon, and made basic with solid potassium carbonate. The liberated base was e 1- tracted into ethyl acetate, the solution was dried and decolorized with activated carbon, and the ethyl acetate was removed in vacuo. The residue was dissolved in ether, again decolorized with activated carbon, and the ether was removed in vacuo, finally at C. and 0.01 mm. for three hours. After filtration through a layer of a filter aid on a sintered glass funnel, the analytically pure 3-(2-methyl-1-piperidyl) propyl 4-butylami- :13 no-2=hydroxybenzoate (119:2 .g.) was zobtained as a nearly colorless, yeryzviscous oil.

Other tertiary-aminoalkyl l-alkylaminoeZ-h-ydroxybenzoates prepared according to the above procedures include those given in Table 3. Since most of these esters are oils, the melting points of their flavianate salts are given. Melting'points of the solid basic esters .and their hydrochloride acid-addition salts where prepared, are given in the footnotes. All melting points :given in Table E are corrected.

The fiavianate salts were prepared thy treating ethanolic solutions of the basic esters with an excess of fiavianic acid solution-in absolute ethanol). These orange to orange red colored crystalline salts were recrystallized from dilute ethanol .or from glacial acetic acid.

TABLEE 5 COO(OH2)n-NRR n m eas s:

-2 Manor. ism-193.2 2 N(CE3)2 l74.0-l77.8 2- (CH3)2. isal-134.0 2 moles... 186.0-1815 2 Nosnw nu mu-215.0 2' mit-186.8 2 was. 0-170. 0 2 '226. 6-228. 4 a 8.,- 179. 7-180. 8 3' uses-159.4 3 MIG-149.3 s 184. 2-118516 a 176. (kl 78:0 s NOuH12 157.0'l59;2 a NO4H80 lers-191.0

b NOsH12=2-methyl-l-piper dyl.

@ With decomposition. I

I Pierate melted at l43.5-l45.5 O. and dihydrochloride melted at l62.0l66.0 C. I

s Dihydrochloride melted at l7l.7 C. (with decomposition).

h Basic ester melted at 62.864.0 O. t

i Diflavianate.

k Basic ester melted at 67.568.4 O. o

1 Dihydrochlorido monohydrate melted at ll7'.0l20.2 G.

veniently prepared by reductively alkylating with an alkanal the corresponding tertiaryaminoalkyl 4 amino 2 benzyloxybenzoates, which were described hereinabove under Section 5. Such a preparation :is exemplified by treating a mixture of '2-.(2,5-.dimethyl-;1-pyrtional tertiary-=aminoalkyl @alkylamino e-diinethylaminobutyl lrdliilyltethyl 4-amino-2-benzylo:rybenzoate sand n-butyraldehyde with chemical reducing agents, such .as zinc dust and acetic acid, or with hydrogen under pressure in the presence of a hydrogenation catalyst such as platinum, palladium or Raney niokel.

Alternatively, the intermediate tertiary-aminoalkyl 4-a1kylamino-2-benzyloxybenzoates were prepared by -esterify'ing the corresponding -alkylamino-Zbenzyloxybenzoic acids. This preparation and the preparation of the intermediate acids are illustrated by the following series of equations, wherein R' is aloweralkyl group and X, NRR' and B have the meanings designated hereinabove Thus, in Step VI, a lower alkyl 4-nitro-2-benzyloxybenzoate (A'), described hereinabove under Section 3, is reduced to the corresponding 4- amino ester (F), which in Step VII is alkylated to form the related 4-alkylainino ester (G). Saponification of this 4-alkylarnino ester (G) in Step VIII yields the parent acid (H) which when esterified in Step IX produces the desired tertiary-aminoalkyl 4 alkylamino-2-benzyloXybenzoate (J). The alkylation in Step VII can be done reductively as described hereinabove using an alkanal or directly using an alkyl ester of an inorganic acid, e.:g., alkyl halide, alkyl sulfate, etc., in the presence of an acid acceptor generally suitable forsuch purpose, such as potassium carbonate .or sodium carbonate. The esterification Step IX can be carried out by difierent procedures such as: first converting the acid (H) to the acid chloride and treating the "latter with tertiary-aminoallzanol of the formula RRN-X-Olt! directly treating the acid (H) with a tertiaryaminoalkyl halide of the formula RR'N-iohalogen. Alternatively, the basic ester (J) can be prepared as illustrated by Step X, by an ester exchange reaction between the lower alkyl ester (G) and a tertiary-aminoa kanol of the formula RRN--X-OH.

.Specific embodiments of the foregoing preparations of the .tertiary-aminoalkyl 4-alky1amino 15 Z-benzyloxybenzoates are presented in the following section.

7. Tertiary-aminoalkyl aZIcyZamino-Z-benzylozybeneoates Preparation of these esters from the corresponding 4-a1nino basic esters is illustrated by the following preparation of 2-dimethylaminoethyl l-n-butylamino-2-benzy1oxybenzoate: To a stirred, refluxing mixture of 40.6 g. of 2-dimethylaminoethyl 4-amino-2-benzyloxybenzoate, 33.8 g. of zinc dust, 32.8 g. of glacial acetic acid and 400 ml. of benzene was added 11.3 g. of nbutyraldehyde during twenty minutes. Stirring and refluxing was continued for an additional one hour period, the mixture was filtered hot, and the filter-cake was washed with dilute acetic acid and with benzene. The filtrate was made basic with ammonium hydroxide solution, mixed well, and the benzene layer was separated and dried. The benzene was distilled in vacuo and the residual oil was dissolved in dilute hydrochloric acid. The acidic solution was decolorized and the base liberated with solid potassium carbonate. The base was extracted with ethyl acetate, and the extract was decolorized and evaporated in vacuo, finally at 0.01 mm. and 100 C. The residual crystalline base was analytically pure 2-dimethylaminoethyl 4-n-butylamin0-2- benzyloxybenzoate, M. P. 46.0-53.9 C. (corr.).

When in the foregoing procedure propionalciehyde was substituted for n-butyraldehyde, the resulting product was 2-dimethylaminoethyl 4- n-propylamino-2-benzyloxybenzoate, M. P. 71.5- 72.7" C. (corr.).

Illustrative of the other above-described method of preparing the intermediate tertiary-aminoallryl 4-alkylamino-Z-benzyloxybenzoates, i. e., starting with a lower alkyl -nitro-Z-benzyloxybenzoate and the final step being the esterification of a 4-alkylamino-2-benzyloxybenzoic acid,

is given as follows in the preparation of 3-dimethylaminopropyl 4 n-butylamino-Z-hydroxybenzoate: The reduction of ethyl 4-nitro-2-benzyloxybenzoate by means of iron-hydrochloric acid in dilute alcoholic solution gave a 95% yield of ethyl 4-amino-2-benzyloxybenzoate, needles from benzene, M. P. 128.6-129.2 C. (corr.). 4.9 g. f n-butyraldehyde was added dropwise to a refiuxing, stirred mixture of 15.0 g. of ethyl 2- benzyloxyi-aminobenzoate, 14.5 g. of zinc dust, 13.7 g. of glacial acetic acid and 200 ml. of benzene during a period of twenty minutes. The mixture was then refluxed with stirring for another hour. iize reaction mixture was filtered, and the filter cake was Washed with benzene and with dilute acetic acid. The combined filtrates were made basic to litmus with ammonium hydroxide and the benzene layer was separated, dried and evaporated to dryness in vacuo. The residue on crystallization from n-hexane gave an 87% yield of ethyl 4-n-butylamino-2benzyloxybenzoate, M. P. 51.6-52.6 C. (corr.). Hydrolysis of this ester by means of aqueous-alcoholic potassium hydroxide solution for one hour gave a quantitative yield of -n-butylamino-2-benzyloxybenzoic acid, leaflets from dilute ethanol, M. P. 108.0- 108.8 C. (corr.).

To an ice-cooled mixture of 50.0 of pure thionyl chloride was gradually added 15.0 g. of in-butylaniino-2-benzyloxybenzoic acid with stirring. The mixture was held at C. for three hours, diluted with 200 m1. of absolute ether, and kept at 0 C. overnight. The resulting crystals were filtered and washed with absolute ether. This material was then added in one portion to a solution of 5.2 g. of B-dimethylaminopropanol in ml. of dry benzene. The resulting mixture was warmed slowly to 50 0., mixed well, and shaken up with dilute sodium carbonate solution. The benzene layer was extracted twice with 5% hydrochloric acid solution; the acidic extracts were made basic with potassium carbonate; and the liberated base was taken up in ethyl acetate. After drying and decolorizing the solution with activated carbon, the ethyl acetate was removed in vacuo, finally at 0.01 mm. and 100 C. There was thus obtained a 76% yield of analy ically pure B-dimethylaminopropyl bn-butylamino-Z- benzyloxybenzoate, as a viscous oil. Treatment of an ethanolic solution of the ester with an excess of fiavianic acid (5% solution in absolute ethanol) gave a crystalline flavianate, which formed orange-red prisms from dilute ethanol. M. P. 1814-1831? C. (corr.).

Additional tertiary-aminoalkyl e-alkylamino- 2-benzyloxybenzoates prepared according to the foregoing describ procedures are given in Table i1. Since these basic esters are viscous oils, the melting points or their flavianate salts are given.

TABLE F ITIHRII O CHzCoH:

| C O O(CH2)..NRR

u Flavisnate. R NRR M. P. C. corr.)

2 l I(OHm. 168.6-1700 (doc) 2 1\T(CH? 1780-1785 (dec) 2 170.0. (a) 151.5.

3 141.0 b 3 .F-IQSJJ (doc). 3 NCSH 180.8-1003 (doc). 3 N(CH3)2..... 182.4l83.4.

Tertiary-aminoalkyl is 'CH(CE3)CH2N(CH3)2 or 3-dimctliylam1no-2-propyl.

b Diilavianate.

Additional tertiary-aminoalkyl 4-alkyla1nino- Z-benzyioxybenzoates which can be prepared cording to the foregoing procedures include the following: e-dimethylaminobutyl 4-ethylamino- 2-benzyioxybenzoate; 2-di-n-butylaminoethyl 1- isobutylamino-Z-benzyloxybenzoate; 2-(l-pyrrolidyl) ethyl 4 .-n-hexylamino-2-benzyloxybenzoate; 3 (2 methyl 1 pyrrolidyDpropyl methyl-amino-2-benzyloxybenzoate; and 2-(2,5- dimethyl-l-pyrrolidyl)ethyl e-n-propylamino-2- benzyloxybenzoate.

The above-described tertiary-aininoalkyl 4-allzylainino il benzyioxyhemoates are readily debenzylated by catalytic reduction to form the cozrcsponding tertiary-aniinoalkyl -a'ilzylaminm Q-hydroxybenzoates, which have been described hereinabove under Section 6. Illustrative of this procedure is the following preparation of 2-di-- methyiaminoethyl i-n-butylamino-2-hydruxybenzoate: To a solution of'25.0 g. of Z-dirnethylaminoethyl 4-n-butylamino-2-benzyloxybenzoate in a mixture of 20 ml. of water, 12 ml. of concentrated hydrochloric acid and ml. of ethanol was added 2 grams of 7% palladium chloride on charcoal. The mixture was treated with hydrogen at 45 C. and 50 lbs. pressure until hydrogen uptake ceased (thirty minutes). The catalyst was filtered off and the filtrate was neutralized with solid sodium bicarbonate. The alcohol was acumen:

removed in- 'vacuo- -and the basewas extracted into ethyl acetate. Atter drying; and 'decolorizing the solution with activated charcoal, the ethyl acetate was removed in yacnp; and residual base was 'purifiedby dissolving itin dilute hydrochloric acid, decolorizing 1the;solution with active charcoal, liberating- .said base by addition of alkali, and removing the-solvent by distilling in high vacuo. The tu es; ethylaminqethyl 4-n-bu'tylamino-2 hydroikybenzoate was a viscous oil, whose fiavianate melted at 174.0-17'7.8 C. (corn) Other tertiary-aminoalkyl 4-alkylamino-2-hydroxybenzoates which can be prepared according to the above procedure are disclosed. hereinabove under Section 6.

This application is a division of our copending aplication, Serial No. 168,842, filed June 1'7, 1956.

We claim:

l. A basic ester having the formula where R" is a lower alkyl radical and X is a lower alkylene radical having 2-4 carbon atoms.

3. A basic ester having the formula NHR -X-NRR' where R is a lower alkyl radical, X is a lower alkylene radical having 2-4 carbon atoms and NRR' is a l-piperidyl radical.

4. A basic ester having the formula where X is a lower alkylene radical having 2-4 carbon atoms.

5. A basic ester having the formula 0O-X-NRR' where X is a lower alkylene radical having 2-4 carbon atoms and NRR is a l-piperidyl radical.

6. A process ol-prep g a basic ester having the formula F u 'NHR' 7. A process according to claim 6 where NRR is a di(lower alkyl) amino radical and the catalyst is a palladium catalyst.

8. A process according to claim 6 where NRR is a l-piperidyl radical and the catalyst is a palladium catalyst.

9. A process of preparing a basic ester having the formula where X is a lower alkylene radical having 2-4 carbon atoms, which comprises catalytically hydrogenating in the presence of a palladium catalyst the corresponding 2-benzyloxy basic ester 7 having the formula where X is a lower alkylene radical having 2-4 carbon atoms.

4-n-buty1amino-2- 4-n-buty1amino-2- 4-n-butyiamino-2- References Cited in the filo of this pctant UNITED STATES PATENTS Number Name Date 1,317,250 Wfldman Sept. 30, 1919 FOREIGN PATENTS Number Country Date 317,296 Great Britain 1830 349,640 Great Britain 1931 

1. A BASIC ESTER HAVING THE FORMULA 